One of the central issues in immunology concerns the way in which the immune system is able to discriminate between self and non-self molecules, so that an immune response may be mounted to foreign pathogens while the body's own constituents are tolerated. This ability is, however, impaired in some patients and this results in autoimmune diseases in which the patients' own tissues are damaged by their immune system. A better understanding of the mechanisms of tolerance is required to further the basic knowledge of the immune system and to develop insights into how tolerogenic mechanisms break down, leading to a variety of autoimmune conditions. The most important cell type upon which tolerance must be imposed is the T lymphocyte which matures in the thymus. Recently, the way in Which T cells become tolerant to the antigens present in the thymus has been characterized, but it is not clear how responses to extra-thymic molecules are avoided. Therefore, the primary aim of this proposal is to investigate the mechanisms by which tolerance to self molecules not expressed in the thymus is imposed and maintained. In order to investigate these processes, transgenic mouse models will be used which produce in defined extrathymic sites antigens and antigenic peptides that have known structures and which can be seen by monoclonal antibodies. Other transgenic mice will be obtained in which the majority of T cells express receptors that are specific for the antigens used and that can be detected by appropriate monoclonal antibodies. The activity, phenotype and fate of the specific T cells will be determined in double transgenic offspring of matings between these two sets of transgenic mice and the conditions favoring autoimmunity or tolerance will be established. The effect of various antigenic peptides on T cell responsiveness will be studied with a view to blocking in vivo responses. This knowledge may lead to new methods of therapy and prevention of autoimmune diseases. It may also help devise strategies for boosting weak immune responses, and therapeutic immunotherapies directed against antigens encoded in defined tissues by oncogenes.